The regeneration of amputated digits in mice is a regeneration model for mammals that is similar to fingertip regeneration noted in humans. Using this model we have discovered that skeletal regeneration can be induced from non-regenerating amputation injuries by treatment with either BMP7 or BMP2. This BMP-induced regeneration response provides a unique opportunity to study underlying molecular and cellular mechanisms that are activated during mammalian regeneration. In this application BMP-induced regeneration will be studied utilizing a transgenic BMP responsive reporter mouse line (BRE:Gfp) to investigate early events associated with the regenerative response. We will test the hypothesis that BMP responsive cells at the amputation injury are directly stimulated to proliferate and/or initiate chondrogenesis via the induction of SOX9. We also will use Laser Capture Microdissection to isolate cells within the BMP response domain for microarray analyses, to test the global hypothesis that BMP activates multiple local signaling cascades that are necessary for induced regeneration. The proposed research will provide a foundation for exploring the role that BMP signaling plays in transitioning a wound healing response into an organized regenerative response. PUBLIC HEALTH RELEVANCE: Mammals, including humans, are not known for their regenerative capacity, but we have recently shown that digit regeneration in post-natal mice can be induced by treatment with either BMP2 or BMP7. Using this model we will explore how BMP signaling transitions a wound healing response that results in scar formation, into a complex response that coordinates the regeneration of multiple tissues (including bone) into a functional structure. Completion of these studies is expected to impact the design of future therapies for treating acute amputation injuries in humans.